HU186526B - Process for producing optically active 1-alkanone derivatives substituted at the 1 position with and aromatic group - Google Patents

Abstract

A manufacturing method is described for the preparation of optically active 1-aromatic-group-substituted-l-alkanones of the formula wherein Ar is an atomic group, X is hydrogen or sulfonyloxy and R is a saturated aliphatic group. An optically active alkane acid halide of the formula wherein Y is halogen, is allowed to react with an aromatic compound in the presence of a Lewis acid. The optically active 1-aromatic-group-substituted-1-alkanones are useful intermediates in the preparation of optically active alpha-arylalkanoic acids, which are useful as pharmaceutical, e.g. anti-inflammatory, analgesic and anti-pyretic, agents and as insecticidal agents.

Description

The present invention relates to a process for the preparation of optically active 1-alkanone substituted in the 1-position by an aromatic group. These compounds are useful in the preparation of optically active alpha-aryl-alkanoic acids, their esters and their pharmaceutically acceptable salts which are useful in medicine and agriculture.

Numerous alpha-aryl-alkanoic acids, i.e. 2-aryl-alkanoic acids, have already been described and have proven useful in medicine and agriculture. Examples of such compounds are disclosed in U.S. Pat. U.S. Pat. The process for preparing these types of compounds is described in 4.135.051, 3.975.431, 3.658.863, 3.663584,

3.658858, 3.694.476 and 3.959.364. U.S. Pat. Recently, various procedures have been described in U.S. Patent 2,042,543. United Kingdom Patent Publication No. 8,005,752, filed September 24, 1980 and filed February 20, 1980. United Kingdom Patent Application Serial No. 0034871; European Patent Specification, published September 2, 1981, filed February 23, 1981; and Tetrahedron Letters, 22, (43), 4305-4308 (1981).

According to the present invention, an optically active 1-alkanone derivative of the formula (I) substituted in the 1-position with an aromatic group is prepared by reacting an optically active alkanoic acid halide of the formula (III) with an aromatic compound of the formula (IV) and in the presence of Lewis acid. In the formulas

Ar is phenyl or naphthyl optionally substituted with one or two C 1-6 alkyl or C 14 alkoxy groups,

R is C 1-4 alkyl,

X is halogen, C 1-4 alkylsulfonyloxy, or phenyl or naphthylsulfonyloxy,

Y represents a halogen atom such as chlorine or bromine and * represents an asymmetric carbon atom.

Optically active 1-alkanone derivatives substituted in the 1-position with an aromatic group are valuable intermediates in the preparation of alpha-arylalkanoic acids, as well as their esters and pharmaceutically acceptable salts thereof. The latter compounds are useful as active ingredients in drugs such as anti-inflammatory and analgesic formulations and insecticides.

The C 1-6 alkyl group may be straight or branched, for example methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, tert-butyl, n-pentyl, isoamyl or hexyl group.

Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl or pentyl.

X is halogen (i.e., bromine, chlorine or iodine) or C 1-4 alkyl or arylsulfonyloxy.

Preferred alkylsulfonyloxy groups include methanesulfonyloxy, ethanesulfonyloxy and butane-sony phenyloxy.

Optically active 1-alkanone derivatives substituted at the 1-position with an optically active compound of the formula I are new compounds whose preparation was previously unknown.

The compounds of formula (I) of formula (II) can be converted to optically active compounds in which Ar and R are as defined above, ^R2 is hydrogen, C1-4 alkyl or C1-4 hydroxyalkyl. Some of these, such as (+) - alpha- (6-methoxy-24-acetyl) propionic acid, used as a raw material for the production of agricultural chemicals or pharmaceuticals, are significantly more effective than the corresponding racemic chemical tax.

Although optically active 1-alkanone derivatives substituted in the 1-position with an aromatic group are important intermediates in the synthesis of various optically active compounds, methods for their preparation are not known. However, the process of the present invention provides the optically active compounds of formula (I) with favorable yield and the use of cheap and readily available optically active compounds as raw materials.

According to the invention, an optically active alkanoic acid halide of formula (III) wherein F and X are as defined above, Y is a halogen atom, preferably chlorine or bromine, is reacted with an aromatic compound of formula (IV) wherein Ar is as defined above. by the so-called Friedel-Crafts reaction in the presence of a Lewis acid, thereby obtaining the optically active compound of formula (I).

It is known in the literature that in the Friedel-Crafts reaction between optically active halides of 2-position asymmetric carbon atoms and aromatic compounds, the 2-position carbon is a secondary carbon such as phenyl-para-tolylacetyl chloride, the resulting alkanone derivatives substituted at the 1-position with an aromatic group lose their optical activity and the reaction results in a racemic product. (See H. Hart, Friedel Crafts and Related Reactions, ed. GA Olah, 1, 1009-1010, Interscience Publishers, New York and London, 1963, W. Bleazard E. Rothstein, J. Chem. Soc., 1958, 3789). )

It is therefore surprising that in the process of the invention, when an optically active alkanoic acid halide of formula (III) is reacted with an aromatic compound of formula (IV) in a Friedel-Crafts reaction, the compound of general formula (I) is an optically active? -alkanone derivative substituted in the 1-position by an aromatic group.

The starting material of the process of the present invention is an inexpensive and readily available optically active alkanoic acid halide of formula (III), a compound of formula (VI) wherein R is methyl, or an optically active alpha amino acid (V). A compound of formula (I) may be prepared, for example, as shown in Reaction Scheme A. All the reaction steps outlined can be carried out without loss of optical purity. In the formulas listed in Scheme A, R, R ¹ , X and Y are as defined above, R ⁴ is alkyl having 1 to 4 fibers.

According to the invention, the optically active alkanoic acid halide of formula (ΠΓ) is reacted with an approximately equimolar amount of the aromatic compound of formula (TV) in the presence of a Lewis acid. As Lewis acid, for example, the following compounds may be used:

organic salts of aluminum, copper, magnesium, calcium, zinc, cadmium, barium, mercury, tin antimony, bismuth, manganese, iron, cobalt, nickel or palladium such as acetate, propionate, benzoate, trifluoromethanesulfonate, methanesulfonate etc. . or an inorganic salt such as chloride, bromide, iodide, sulfate, oxide, etc. or boron tritluoride, etc.

Particularly preferred are metal halides, such as aluminum chloride, zinc chloride, cobalt chloride, zinc bromide, tin (II) chloride, ferric (II) chloroform, ferric (III) chloride, nickel bromide, cadmium chloride, magnesium chloride, mercury (I) chloride, mercury (II) chloride, antimony chloride, barium chloride, calcium chloride, copper (I) chloride, copper (II) chloride, manganese chloride, tin (IV) chloride, bismuth chloride or palladium trichloride.

Preferably, the following Lewis acids are used: aluminum chloride, aluminum bronze, stannous chloride, ferric chloride, zinc chloride and boron trifluoride.

When starting from a compound of formula (ΠΙ) containing a sulfonyloxy group in the X position, the use of a relatively weak, i.e., slightly acidic Lewis acid such as ferric chloride, ferric sulfate is preferred. such as magnesium bromide or zinc chloride. Iron (HI) sulfate and ferric chloride are particularly preferred for this purpose.

Usually, it is sufficient to take equimolar amounts of the Lewis acid with the starting compound of formula (IH). If, on the other hand, the aromatic compound of formula (IV) has a functional group that readily binds the Lewis acid. Such a compound is, for example, acetanilide, then favorable results are obtained only if the Lewis acid is taken in excess.

The reaction according to the invention is conveniently carried out in the presence of a solvent. A variety of compounds conventionally used for this purpose in Friedel-Crafts reactions, such as S2-disulfide, 1,2-michloroethane, petroleum ether, hexane, nitromethane or nitrobenzene, can be used. However, when starting with a compound of formula (ΠΙ) containing a sulfonyloxy group at X, it is preferable to use a solvent which is relatively polar, such as nitromethane or nitrobenzene.

The reaction is usually carried out at a temperature of -10 ° C to 100 ° C, but preferably at a reaction temperature of 0 ° C to 50 ° C, to allow the target compound to be formed rapidly. After completion of the reaction, water may be added to the reaction mixture, and the product may be isolated by conventional methods such as extraction with an organic solvent in Friedel-Crafts reactions. This yields a good yield of the compound of formula I, which is obtained in a more or less optically pure form,

The invention is illustrated in detail by the following examples.

The compounds of formula (II) which can be prepared from the compounds of formula (I) according to the invention include a number of compounds which can be used as pharmaceuticals or as agrochemicals. Typical examples of these valuable compounds are:

alpha- (4-isobutyl-phenyl) -propiC'-acid (ibuprofen), (+) - 2- (6-methoxy-naphth-2-yl) -propionic acid (naproxen) and alpha- [4- (1-oxo) 2 4-isoindolinyl) phenyl] propionic acid (indoprofen, an anti-inflammatory agent).

Other typical examples are:

alpha- (2-thienyl) -propionic acid, alpha- (4-acetylamino-o-phenyl) -propionic acid methyl ester, alpha- [4- (tert-butyl) -phenyl] -isoyaleric acid, alpha- Methyl (4-alkoxyphenyl) -isovaleric acid methyl, alpha (4-biphenylyl) -propionic acid, methyl [alpha] - [4- (difluoromethoxy) -phenyl] -isovaleric acid and alpha- (4-alkoxy) phenyl) propionate: av methyl ester.

The latter compounds are important intermediates in the synthesis of gj Anti-inflammatory drugs and insecticides.

Example 1 (Reaction Scheme B)

A mixture of 24.11 g (0.2041 mole) of ethyl L - (+) - lactic acid and 50 ml of anhydrous pyridine is stirred in an ice bath. Methylsulfonyl chloride (17.0 mL, 25 (2 g, 0.220 mol)) was added dropwise over 20 minutes, and the reaction mixture was stirred at this temperature for 1 hour, then at room temperature for an additional 1 hour. The extract was washed with water (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to a red oily residue.

32.20 g of ethyl (-) - 2-methylsulfonyloxypropionic acid ethyl ester are obtained in the form of a colorless liquid, m.p. 97-102 C / 2 tons. Yield: 82.0%.

= -50.55 ° (c = 1.00, chloroform)

MMR (deuterochloroform) δ values: 1.30 (311, triplet, J = 7 Hz), pH 1.59, doublet, J = 7 Hz),

3.11 (3Η, singlet), 4.23 (2H, quartet J = 7 Hz), 5.07 (1H, quartet, J = 7 Hz).

Analysis of C ^ Hj? Calculated: C, 36.72; C, 6.17; S, 16.34. Found: C, 36.54; 5, 5.99; S, 9 (S9).

Example 2 (Reaction to Reaction C / Jat)

Potassium hydroxide (5.02 g, 0.0895 mol) was dissolved in water (50 ml) and the solution was stirred at -20 ° C and 14.46 g (0.0737 mol) of (-) - 2-methyl- sulfonyloxypropionic acid ethyl ester prepared according to Example 1. After stirring for 5 hours at this temperature, the reaction mixture was adjusted to pH less than 1 with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 30 mL). Anhydrous sodium sulfate was added to the organic solution followed by anhydrous magnesium sulfate for drying. then concentrated in vacuo.

11.83 g of (-) - 2-methylsulfonyloxypropionic acid are obtained in the form of crystals, m.p. 65-72 ° C. Production of 4%.

(? 1 D = -49.81 ° (c = 1.00, chloroform).

Infrared spectrum (potassium brornide lozenge):

3025,1748,1360,1178,952,840,832,528 cm ^-1 .

Δ-values: 1.67 (3H, doublet, J = 7Hz), 3.19 (3H, singlet), 5.17 (1H, quartet, J = 7Ht), 9.78. (IH, singlet).

Analysis calculated for C ₄ H _g O ₅ S: C, 28.57; H, 4.78; S, 19.07; Found: C, 28.58; H, 4.79; S, 18.91. %.

Example 3 (Reaction Scheme D)

(-) - 2-Methylsulfonyloxypropionic acid (3.36 g, 0.02 mol), prepared according to Example 2, and thionyl (29 ml, 4.8 g, 0.04 mol). chloride is added at room temperature. Anhydrous pyridine (3 drops) was added and the reaction mixture was heated at 80-90 ° C for 3 hours. The excess thionyl chloride was evaporated in vacuo (2198 Pa) at a bath temperature of 80 ° C and the residue fractionated in vacuo.

3.16 g of (-) - 2-methylsulfonyloxypropionic acid chloride are obtained in the form of a colorless oil, m.p. 70-74 ° C.

MmR (deuterochloroform) δ values: 1.67 (3H, doublet, J = 7Hz), 3.14 (3H, singlet), 5.17 (1H, quartet, J = 7Hz).

Analysis calculated for C ₄ H ₇ ClO ₄ S: C, 25.74; H, 3.78; S, 17.18. Found: C, 25.77; H, 3.89; S, 17 43%.

Example 4 (Preparation of Compound IX)

2.54 g (0.02 mole) of R - (+) - 2-chloropropionic acid chloride (S.-C J. Fu, SM Bimbaum and JP Greenstein, J. Am. Chem. Soc., 76, 6054). (1954) and 7 ml of benzene were stirred in an ice bath. Anhydrous anhydrous chloride (3.00 g, 0.0225 mol) was added in small portions over about 15 minutes, so that the reaction temperature did not exceed 10 ° C. The reaction mixture was stirred for 20 minutes at the same temperature and then for 1 hour at room temperature. Water (30 mL) was then added under ice-cooling, ensuring that the temperature of the reaction mixture did not exceed 25 ° C. Concentrated hydrochloric acid solution (5 ml) was added, the mixture was extracted twice with 50 ml of ether and the extract was washed twice with 30 ml of water. The extract was dried over anhydrous magnesium sulfate, concentrated in vacuo and the oily residue fractionated in vacuo.

291 g of (-) - 2-chloro-1-phenyl-1-propanone are obtained in the form of a colorless liquid, m.p. 110 ° C / 1465 Pa. From production [a] |? -15.26 ° (c = 1.00, chloroform).

Δ values: 1.68 (3H, doublet, J = 6H), 5.07 (1H, quartet, J = 6H), 73-7.6 (3Hi multiplet), δ 8.1 (2H, multiplet).

The compound was found to be optically pure on the basis of the MMR ₃ spectrum using an optically active compound, tris [3- (trifluoromethylhydroxy-methylene) -d-camphatoTato] -europium (Eu / TFC /) in carbon tetrachloride.

Analysis calculated for C ₉ H 8 ClO: C, 64.10; H, 538; S, 21.03; Found: C, 64.00; H, 5.48; S, 2096.

Example 5 (Reaction Scheme E)

R - (+) - 2-chloropropionic acid chloride (0.206 g, 0.00162 mol) and isobutylbenzene (0.025 g, 0.00192 mol) were dissolved in 1 ml of carbon disulfide and the solution was -20 and -25 ° C. and stirring. To the solution was added 0.213 g (0.0016 mol) of anhydrous aluminum chloride over 10 minutes, and the reaction mixture was stirred for 10 minutes at the same temperature and then for 30 minutes at -10 ° C. Water (10 ml) was added with cooling followed by 2 ml of concentrated hydrochloric acid. Extraction was carried out twice with 20 ml of food, the extract was washed twice with 10 ml of water, dried over anhydrous magnesium sulfate and vacuum-dried; concentrated.

The residue was purified by column chromatography over silica gel (dichloromethane eluent). 0.310 g of (-) - 2-chloro-1- (44-isobutylphenyl) -1-propanone are obtained in the form of colorless crystals, m.p. 79 ° C. Yield 863% · i <x] D = -29.08 ° ^ö (c = 1.00, chloroform).

Infrared (potassium bromide pellet): 2950,1685,1605,1265,1188,957,645 ππί ¹ .

Example 6 (Reaction Scheme F)

1.196 g (0.006408 mole) of (-) - 2-methylsulfonyloxlpropionic acid chloride and 1390 g (0.009612 mole) of isobutylbenzene are dissolved in 3 ml of anhydrous nitrobenzene and the taste solution is stirred under ice-cooling. Anhydrous ferric chloride (1.416 g, 0.008729 mol) was added in small portions over 10 minutes, and the reaction mixture was stirred at room temperature for 9 hours. Water (20 mL) was added, the mixture was extracted with water (3 x 20 mL), the extract was washed with water (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column eluting with dichloromethane.

1331 g of crude product are obtained, which according to gas chromatography contains about 95% of the target compound. Recrystallization from hexane gave 1.005 g of (-) - 2-methane-5-sulfonyloxy- (4-isobutylphenyl) -1-propanol as colorless needle crystals, m.p. 81-82 ° C. Yield: 55.1%.

[ajjj ⁴ »-52.48 ° (c = 1.00, chloroform).

Infrared spectrum (potassium bromide lozenge):

2960, 1697, 1609, 1367, 1240, 1180, 1023, 930, 821,745,525 ^cm-first

Δ values: 0.93 (6H, doublet, J = 7Hz), 1.5-2.1 (1H, multiplet), 1.65 (311, doublet, J = 7Hz) ), 2.54 (2H, doublet, J = 7Hz),

3.12 (3H, singlet), 6.03 (1H, quartet, J = 7Hz), 737 (2H, doublet, J = 9Hz), 7.87 (2H, doublet, J = 9Hz).

Example 7 (Reaction Scheme G illustrates the reaction)

0.80 g (0.0063 mole) of R - (+) - 2-chloropropionyl chloride and 0.81 g (0.0075 mole) of anisole are dissolved in 4 ml of S-disulfide at -20 and -25 ° C. Stir at C and add 1.00 g (0.0075 mol) of anhydrous ammonium chloride. The reaction mixture was stirred for one minute at this temperature and then for 1 hour at -10 to -5. The mixture was poured into about 2 mL of ice water and extracted twice with 15 mL of ether. It was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by column chromatography (silica gel, eluent: ethyl acetate and hexane).

(-) - 2-chloro-1-methoxyphenyl-1-propanone is obtained as a colorless oily substance.

[α] D 20 = 503 ° C (c = 0.84, chloroform)

IR (pure substance examination): 1690, 1605,1515,1260,1173,1032,958,847 ^cm-f.

MMR spectrum (deuterochloroform) δ values:

1.70 (3H, doublet, J = 6Hz), 3.82 (311, singlet), 5.15 (1H, quartet, J = 6Hz), 6.90 (2H, doublet, J = 9Hz), 7 , 84 (211, doublet, J = 9Hz).

Example 8 (Reaction Scheme H)

Beta-methoxynaphthalene (0.791 g *, 0.005 mol) and (S) -2- (methylsulfonyloxy) propionyl chloride (0.933 g, 0.005 mol) were dissolved in anhydrous o-dichlorobenzene (5 ml) and stirring at room temperature. To the solution was added 296 mg of anhydrous iron (III) sulfate, prepared by drying iron (III) sulfate heptahydrate for 3 hours under vacuum at 150 ° C and stirring the reaction mixture at 70 ° C for 18 hours. in an argon gas stream. Water (30 mL) was added and the mixture was extracted with dichloromethane (2 x 30 mL). The organic extract was washed with water (2 x 10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was chromatographed on a silica gel column eluting with dichloromethane. The material thus purified was (S) -1- (6-methoxy-2-naphthyl) -2- (methylsulfonyloxy) -1-propanone, colorless, glassy.

(a] D ⁶ = -35.6 ° (c = 0.982, chloroform).

It is crystallized from methanol and then recrystallized from the same solvent. Colorless needles, m.p. 156-157 ° C. _t pain) ⁶ = -36.0 ° (c = 0.806, chloroform).

Infrared (potassium bromide pastilles): 1697, 1629, 1490, 1370, 1280, 1196, 1175, 1020, 938,

900323.527 cm ^1st

MMR spectrum (deuterochloroform) δ values:

1.70 (3H, doublet, J = 7Hz), 3.13 (3H, singlet), 3.92 (3H, singlet), 6.16 (1H, quartet, J = 7Hz), 7.1-7.3 (2H, multiplet), 8.37 (1H, broad singlet).

Ι _e calcd for C ₆ H i O ₅ S Calcd: C: C: 58.44, H: 5.12, S: 10 58.42 H, 5.23; S, 10.40% Found 67%.

Example 9 (Reaction Scheme I)

The procedure described in Example 8 was followed, starting from beta-methoxy-naphthalene and (S) -2- (phenylsulfonyloxy) -propionyl chloride. To give (S) -l- (6-methoxy-2-naphthyl) -2- (phenylmethyl 5zulfoni] oxy} -l-propanone as colorless crystals, mp .: 74-75 ° C. Species) ⁰ + 35.1 ⁰ (c = 130, chloroform)

Infrared (potassium bromide pellet): 1702,

1628, 1350, 1275, 1197, 1180, 1020, 934, 910, 899, 759, 623 cm -1.

MMR spectrum (deuterochloroform) δ values:

1.65 (3H, doublet, J = 7Hz), 3.93 (3H, singlet), 5.94 (1H, quartet, J = 7Hz), 7.1-8.0 (10H, multiplet), δ, 33 (1H, broad singlet).

Claims (7)

PATENT CLAIMS 1. Process for the preparation of an optically active compound of formula (I) A 1-alkanone derivative substituted in the 1-position with Ar being phenyl or naphthyl optionally substituted with one or two R 1 is substituted with C 1-6 alkyl or C 1-4 alkoxy C 1 -C 4 alkyl, X is halogen, C 1 -C 4 alkylsulfonyloxy or phenyl or naphthylsulfonyloxy, and a * represents an asymmetric carbon atom, characterized in that an optically an active alkanoic acid halide wherein Y is halogen, X, R and * are as defined above, in the presence of a Lewis acid, with an aromatic compound of formula IV wherein Ar is as defined above. 2. A process according to claim 1, wherein the optically active alkanoic acid halide of formula (Π1) is reacted with the aromatic compound of formula (TV) at a temperature of -10 to 100 ° C. 3. The process according to claim 2, wherein the reaction is carried out at a temperature of 0 to 50 ° C. The process of claim 1 wherein the optically active alkanoic acid halide is a compound of formula III wherein X is alkylsulfonyloxy, wherein Y, R and * are as defined in claim 1. Lewis acid is a relatively weak Lewis acid. The method of claim 4, wherein characterized in that the Lewis acid is iron (III) sulfate, iron (I ') chloride, or aluminum chloride. 6. A process according to claim 1 wherein the optically active alkanoic acid halide is a compound of formula III wherein X is phenylsulfonyloxy, wherein Y, R and * are as defined in claim 1. As claimed in claim 1. 7. A process according to claim 1 wherein R is methyl, wherein X, Y and * are as defined in claim 1, Ar is 6-methoxy-2-naphthyl. with a compound of formula (IV).